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Liver Drug Obeticholic Acid (Ocaliva) Wins Accelerated Approval

Farnesoid X receptor agonist reduces alkaline phosphatase

The FDA has granted accelerated approval to obeticholic acid (Ocaliva, Intercept Pharmaceuticals) for the treatment of primary biliary cholangitis, previously known as primary biliary cirrhosis, in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA. Obeticholic acid is an agonist of the farnesoid X receptor (FXR), a nuclear receptor expressed in the liver and intestine and a key regulator of bile acid, inflammatory, fibrotic, and metabolic pathways.

The approval was based on a reduction in alkaline phosphatase (ALP). An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon the verification of a clinical benefit in confirmatory trials.

The phase 3 POISE trial studied the safety and efficacy of once-daily treatment with obeticholic acid in PBC patients who had an inadequate therapeutic response to, or were unable to tolerate, UDCA. Obeticholic acid, at both a 10-mg dose and a 5-mg dose titrated to 10 mg, in combination with UDCA (or as monotherapy in UDCA-intolerant patients), met the trial’s primary endpoint of achieving a reduction in serum ALP to below a threshold of 1.67 times the upper limit of normal, with a minimum 15% reduction in the ALP level from baseline, and a normal bilirubin level after 12 months of therapy. The primary composite endpoint was met in 46% of patients in the titration group compared with 10% of those receiving placebo added to UDCA (P < 0.0001).

Pruritus was the most frequently reported adverse event associated with treatment with obeticholic acid. In patients who initiated treatment at a 5-mg once-daily dosage and were titrated up to 10 mg once daily, only one patient (1%) withdrew from the study because of pruritus compared with seven patients (10%) in the 10-mg dose group, and efficacy at 12 months was essentially equivalent to that observed in patients who started the study at the 10-mg dose. Based on these results, a 5-mg to 10-mg titration regimen is recommended for obeticholic acid dosing in patients with PBC. Decreases in high-density lipoprotein-cholesterol were observed during treatment.